Clot ablation using focused ultrasound and thrombolytic drugs to treat chronic deep vein thrombosis
Deep vein thrombosis is a debilitating condition that can require rapid intervention to prevent amputation of the affected limb or death. The current interventional approaches are not effective for older, chronic thrombi, characteristic of those found in deep vein thrombosis. Histotripsy is a novel form of therapeutic ultrasound that employs the mechanical action of oscillating cavitation bubbles to ablate thrombi. Preliminary data from Dr. Bader demonstrate that the thrombolytic recombinant tissue plasminogen activator acts synergistically with histotripsy pulses to provide enhanced thrombolysis in highly retracted venous clots. Further studies will elucidate the efficacy and potential risks of histotripsy to ablate venous thrombosis, and provide new information to assist the development of targeted ablation methods to improve thrombolysis in the treatment of currently intractable deep vein thrombosis.
(Left) The generation of histotripsy bubble activity within the clot can be tracked with passive cavitation imaging (PCI) to quantify the mechanical activity of the bubble cloud. (Right) Following insonation, ablation is observed within the clot in locations where strong bubble activity occurred (black arrowhead), as indicated on Masson’s trichrome stains.
Chronic Venous Thrombus Characterization
Venous thromboembolism (VTE) is a major public health problem, affecting 900,000 Americans annually and accruing $10 billion in healthcare costs. The standard treatment, catheter-directed lytics, is not effective for the chronic thrombus components present in 27% to 43% of VTE cases. The unnecessary administration of thrombolytic drugs increases the risk of bleeding complications, warranting alternative treatment profiles for chronic pathologies. Prognostic indicators for personalized guidance of VTE treatment will improve clinical outcomes for chronic VTE patients. To determine these indicators, we perform extensive histological, mechanical, and MR characterization of ex vivo VTE samples provided by our collaborators in interventional radiology and interventional cardiology. Our preliminary data indicate chronic thrombi exhibit structural remodeling via collagen infiltration, and a depletion of red blood cells. An increased stiffness in the collagen-rich thrombus structure can be assessed with ultrasound shear wave elastography. Susceptibility magnetic resonance (MR) imaging provides a means to detect accentuation of the thrombus iron microenvironment due to red blood cells.
Regions of strong collagen infiltration (blue stain indicated by block green arrow, Right Panel), the strongest prognostic indicator of chronic thrombus, are concatenate with regions of dense fibrin (light pink stain indicated by blue arrow in the Center Panel) and platelets (brown stain indicated by yellow arrow, Left Panel). Notably, regions of collagen appear devoid of red blood cells (dark red stain indicated by black arrowhead, center panel). The bar in the lower left corner of each panel corresponds to a 300 micrometer distance.
Collaborative Robots for Administration of Histotripsy Therapy
Histotripsy sources are highly focused to restrict bubble activity in close proximity to the focal zone. For extensive thrombus formation, the source must be rastered mechanically to generate bubble activity throughout the clot burdeon. While convenient for pre-clinical studies, three-axis systems don’t have a sufficient number of degrees of freedom to place the source in an arbitrary position in space, which can make positioning the system difficult relative to the patient anatomy. The need for ease of automation has given rise to so-called collaborative robotic systems, or cobots. Unlike conventional robotic systems, which require some degree of explicit programming to determine movements for the robot, cobots can be programmed via “teach by example,” allowing the user to physically move the system to determine the overall movements to achieve the end goal movement. Further, sensors integrated within cobots ensure they can be operated in close proximity with humans, unlike traditional industrial robotic systems. We envision the flexibility of a cobotic system would enable clinicians to plan out the histotripsy treatment path, utilizing a confocal diagnostic imaging probe to set the treatment path.
Collaborative robotic arm (UR5e, Universal Robots, Inc) rastering a 3D rendering of a histotripsy source. The path of the robot was set using “teach-by-example” mode
Proposed implementation of collaborative robotic arm to mechanically raster histotripsy source
Viktor Bollen, Samuel A. Hendley, Jonathan D. Paul, Adam D. Maxwell, Kevin J. Haworth, Christy K. Holland, Kenneth B. Bader, “In vitro thrombolytic efficacy of single- and five-cycle histotripsy pulses and rt-PA,” Ultrasound in Medicine and Biology, 46(2): 336-349, 2020, doi: 10.1016/j.ultrasmedbiol.2019.10.009
Kenneth B. Bader, Kevin J. Haworth, Himanshu Shekhar, Adam D. Maxwell, Tao Peng, David D. McPherson, Christy K. Holland, “Efficacy of histotripsy combined with rt-PA in vitro,” Physics in Medicine and Biology, 61 (14): 5253-5274, 2016. doi: 10.1088/0031-9155/61/14/5253